The hepatitis C virus (HCV) infects approximately 2% of the global population. The majority (70%) of individuals exposed to the virus develop a persistent, life-long infection that over a period of years can result in cirrhosis of the liver or even hepatocellular carcinoma. It is thought that T cell mediated immune responses are important for spontaneous resolution of infection but the relative contribution of CD4+ and CD8+ subsets are not known. In order to directly address the role of CD8+ T cells during acute HCV infection, chimpanzees will be temporarily depleted of CD8+ T cells prior to challenge with HCV. This experimental approach will address the following aims: 1) To assess how HCV replication and liver pathology is altered by depletion of CD8+ T cells prior to infection, 2) To study the evolution of the CD4+ T cell response to acute HCV infection during the absence and recovery of the CD8+ T cell compartment, and 3) To determine if eliminating the selective pressure mediated by CDS+ T cells alters the evolution of class I and class II MHC restricted HCV epitopes. Results from the experiments proposed in this research plan should contribute to our understanding of HCV pathogenesis by providing a detailed temporal analysis of the kinetics of viral replication and liver pathology during the absence and recovery of the CDS+ T cell compartment following HCV infection. These studies will also provide important new information as to the relative importance of CD8+ and CD4+ T cell responses in the control of HCV infection while determining if a correlation exists between the emergence of antigen specific T cells, the evolution of escape mutations, and the kinetics of virus replication in vivo.